Pediatric Diabetic Ketoacidosis With Hyperosmolarity: Clinical Characteristics and Outcomes.

OBJECTIVE: Studies of hyperglycemic emergencies with hyperosmolality, including hyperglycemic hyperosmolar state (HHS) and "mixed presentation" with features of diabetic ketoacidosis (DKA) and HHS, are lacking in children. Objectives were to determine the incidence of DKA, HHS, and mixed presentation in a pediatric population, to characterize complications, and to assess accuracy of associated diagnosis codes. METHODS: Retrospective cohort study of 411 hyperglycemic emergencies in pediatric patients hospitalized between 2009 and 2014. Hyperglycemic emergency type was determined by biochemical criteria and compared to the associated diagnosis code. RESULTS: Hyperglycemic emergencies included: 333 DKA, 54 mixed presentation, and 3 HHS. Altered mental status occurred more frequently in hyperosmolar events ( P<.0001), and patients with hyperosmolarity had 3.7-fold greater odds of developing complications compared to those with DKA ( P = .0187). Of those with DKA, 98.5% were coded correctly. The majority (81.5%) of mixed DKA-HHS events were coded incorrectly. Events coded incorrectly had 3.1-fold greater odds of a complication ( P = .02). CONCLUSION: A mixed DKA-HHS presentation occurred in 13.8% of characterized hyperglycemic emergencies, whereas HHS remained a rare diagnosis (0.8%) in pediatrics. Hyperosmolar events had higher rates of complications. As treatment of hyperosmolarity differs from DKA, its recognition is essential for appropriate management. ABBREVIATIONS: AMS = altered mental status; DKA = diabetic ketoacidosis; EMR = electronic medical record; HHS = hyperglycemic hyperosmolar state; ICD-9 = International Classification of Diseases, Ninth Revision; ISPAD = International Society of Pediatric and Adolescent Diabetes; NODM = new-onset diabetes mellitus; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

Severe Hypertriglyceridemia due to a novel p.Q240H mutation in the Lipoprotein Lipase gene.

BACKGROUND: Lipoprotein Lipase (LPL) deficiency is a rare autosomal recessive disorder with a heterogeneous clinical presentation. Several mutations in the LPL gene have been identified to cause decreased activity of the enzyme. FINDINGS: An 11-week-old, exclusively breastfed male presented with coffee-ground emesis, melena, xanthomas, lipemia retinalis and chylomicronemia. Genomic DNA analysis identified lipoprotein lipase deficiency due to compound heterozygosity including a novel p.Q240H mutation in exon 5 of the lipoprotein lipase (LPL) gene. His severe hypertriglyceridemia, including xanthomas, resolved with dietary long-chain fat restriction. CONCLUSIONS: We describe a novel mutation of the LPL gene causing severe hypertriglyceridemia and report the response to treatment. A review of the current literature regarding LPL deficiency syndrome reveals a few potential new therapies under investigation.

Child Health Needs and the Pediatric Endocrinology Workforce: 2020-2040.

The pediatric endocrinology (PE) workforce in the United States is struggling to sustain an adequate, let alone optimal, workforce capacity. This article, one of a series of articles in a supplement to Pediatrics, focuses on the pediatric subspecialty workforce and furthers previous evaluations of the US PE workforce to model the current and future clinical PE workforce and its geographic distribution. The article first discusses the children presenting to PE care teams, reviews the current state of the PE subspecialty workforce, and presents projected headcount and clinical workforce equivalents at the national, census region, and census division level on the basis of a subspecialty workforce supply model through 2040. It concludes by discussing the educational and training, clinical practice, policy, and future workforce research implications of the data presented. Data presented in this article are available from the American Board of Pediatrics, the National Resident Matching Program, and the subspecialty workforce supply model. Aging, part-time appointments, and unbalanced geographic distribution of providers diminish the PE workforce capacity. In addition, limited exposure, financial concerns, and lifestyle perceptions may impact trainees. Additional workforce challenges are the subspecialty's increasingly complex cases and breadth of conditions treated, reliance on international medical graduates to fill fellowship slots, and high relative proportion of research careers. The recent limitations on pediatric endocrinologists providing gender-affirming care may also impact the geographic distribution of the subspecialty's workforce. Deliberate actions need to be taken now to continue serving the needs of children.

Growth hormone deficiency and central precocious puberty in Klinefelter syndrome: report of a case and review of KIGS database.

Growth hormone deficiency (GHD) and central precocious puberty (CPP) have each, individually, been described in patients with Klinefelter syndrome. However, the combination of GHD, CPP, and Klinefelter syndrome has never been reported. We described a Klinefelter syndrome patient who developed GHD at age 2 10/12 years and CPP at 8 6/12 years. Despite CPP, GnRH agonist therapy was not initiated because of his excellent predicted adult height. At 11 8/12 years, his height was 164.6 cm, close to his mid-parental target height of 165 cm. We report an additional nine patients with Klinefelter syndrome and GHD from the Pfizer International Growth Study (KIGS) database, none of whom had CPP. We conclude that the combination of GHD and CPP is very rare in Klinefelter syndrome and that CPP is unlikely to compromise final adult height.

The Incidence of Erosive Esophagitis as a Complication of Pediatric Diabetic Ketoacidosis.

INTRODUCTION: Gastrointestinal (GI) symptoms commonly occur during diabetic ketoacidosis (DKA) and typically resolve with treatment. However, GI complications can persist after DKA resolves. The incidence of upper GI bleeding during DKA in adults has been described, with erosive esophagitis one of the most common lesions. The incidence of GI bleeding or erosive esophagitis in children with DKA has not been previously reported. We performed a retrospective chart review of DKA admissions in children 0 to <18 years with type 1 diabetes mellitus (T1DM) at a pediatric hospital between January 2009 and July 2016. Among 395 episodes of DKA over 7.5 years, erosive esophagitis occurred during two DKA admissions (0.5%) and there were no episodes of GI bleeding. Case presentations. Both episodes of erosive esophagitis occurred in adolescent males with known T1DM who presented with severe DKA. Both developed odynophagia after resolution of DKA and were readmitted for DKA recurrence. Upper endoscopy for both patients showed erosive esophagitis. Biopsies were negative for infection, though candida was found during one patient's endoscopy. Both had resolution of their esophagitis symptoms with medication management; neither has had recurrence. CONCLUSION: Erosive esophagitis, a rare complication of pediatric DKA, can manifest with odynophagia or substernal chest pain. This complication can lead to DKA recurrence, likely due to increased insulin resistance from inflammation and pain and from reduced oral intake and insulin administration. Patients with odynophagia associated with DKA should be monitored closely to allow timely evaluation and treatment of esophagitis.

EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic ß-cells.

BACKGROUND: Postnatal expansion of the pancreatic ß-cell mass is required to maintain glucose homeostasis immediately after birth. This ß-cell expansion is regulated by multiple growth factors, including glucose, insulin, insulin-like growth factor (IGF-1) and epidermal growth factor (EGF). These mitogens signal through several downstream pathways (AKT, ERK, STAT3, and JNK) to regulate the survival and proliferation of ß-cells. Survivin, an oncofetal protein with both pro-proliferative and anti-apoptotic properties, is a known transcriptional target of both IGF-1 and EGF in cancer cells. Here, we analyzed the effects of the ß-cell mitogens IGF-1 and EGF on survivin regulation in the established pancreatic ß-cell model cell lines, MIN6 and INS-1 and in primary mouse islets. RESULTS: In pancreatic ß-cells, treatment with glucose, insulin, or EGF increased survivin protein levels at early time points. By contrast, no significant effects on survivin were observed following IGF-1 treatment. EGF-stimulated increases in survivin protein were abrogated in the presence of downstream inhibitors of the Raf-1/MEK/ERK pathway. EGF had no significant effect on survivin transcription however it prolonged the half-life of the survivin protein and stabilized survivin protein levels by inhibiting surviving ubiquitination. CONCLUSIONS: This study defines a novel mechanism of survivin regulation by EGF through the Raf-1/MEK/ERK pathway in pancreatic ß-cells, via prolongation of survivin protein half-life and inhibition of the ubiquitin-mediated proteasomal degradation pathway. This mechanism may be important for regulating ß-cell expansion after birth.

Autoimmune polyglandular syndrome Type 3 and growth hormone deficiency.

The simultaneous occurrence of prepubertal Graves' disease, type 1 Diabetes Mellitus (DM), and Growth hormone deficiency (GHD) is uncommon. GHD has been reported in Autoimmune Polyglandular Syndrome (APS) Type 1 and Type 2 but not in APS Type 3. We report a 3-yr-old boy who presented simultaneously with type 1 DM and Graves' disease. After he developed urticarial rash to Propylthiouracil and Methimazole with persistent thyrotoxicosis, he received 8 millicuries of (131)I at 5 yr of age. We diagnosed GHD at age 8 yr 8 months because of growth deceleration (from 95 to 25%) and abnormal growth rate (3 cm/yr) despite euthyroidism, fair glycemic control, and normal weight gain. Both insulin-like growth factor (IGF) 1 (90 ng/mL; normal 113-261 ng/mL) and IGFBP3 (1.3 mcg/mL; normal 2.1-4.2 mcg/mL) levels were low and peak growth hormone level measured by RIA was 5.2 ng/mL after L-Dopa and insulin tolerance test. The rest of his pituitary functions and magnetic resonance imaging of the pituitary gland were normal. Growth hormone treatment (0.3 mg/kg/wk) was administered at 8 yr 9 months until near final adult height (FAH). Near FAH (172 cm) was close to midparental target height of 180 cm. GHD may be a component of all APS even though it is rare. Growth in treated children with Graves' disease should be followed closely as catch down growth below genetic height potential may be a harbinger of underlying GHD.

Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome?

OBJECTIVE: To examine the risk of obesity and metabolic syndrome in women with a history of gestational diabetes mellitus and in offspring born to mothers with gestational diabetes mellitus. METHODS: A review of studies examining the development of obesity, hypertension, metabolic abnormalities, metabolic syndrome, and type II diabetes in mothers with a history of gestational diabetes mellitus and control mothers, and offspring of mothers with a history of gestational diabetes and control mothers. RESULTS: Longitudinal studies demonstrate that women with a prior history of gestational diabetes mellitus and obesity are at significantly greater risk of developing metabolic syndrome than mothers with no history of gestational diabetes or obesity. The development of metabolic syndrome in children with increasing age is related to maternal gestational diabetes mellitus, maternal glycemia in the 3rd trimester, maternal obesity, neonatal macrosomia, and childhood obesity. CONCLUSIONS: The current prevalence of obesity in both adults and children and associated disorders of blood pressure and lipid metabolism, suggest a perpetuating cycle of increasing obesity, insulin resistance, and abnormal lipid metabolism, which has ominous consequences for future generations.

Pediatric Diabetes Outpatient Center at Rhode Island Hospital: The impact of changing initial diabetes education from inpatient to outpatient.

BACKGROUND: This study compared outcomes and costs for new-onset Type 1 diabetes mellitus (T1DM) patients educated at the outpatient versus inpatient settings. METHODS/DESIGN: Retrospective study examining the following variables: 1) hemoglobin A1c (HbA1c), 2) severe hypoglycemia, 3) admissions for diabetic ketoacidosis (DKA) or ER visits, and 4) healthcare cost. RESULTS: 152 patients with new-onset T1DM from September 2007-August 2009. There were no differences between outpatient group (OG) and inpatient group (IG) in mean HbA1c levels at 1, 2 and 3 years post-diagnosis (OG 8%, 8.5%, 9.3%; IG 8.3%, 8.9%, 9%, p=0.51). Episodes of severe hypoglycemia, DKA, and ER visits were not different between the two groups. Mean total hospital costs for OG and pure OG were significantly less than IG (OG: $2886 vs. IG: $4925, p<0.001), (pure OG: $1044 vs. IG: $4925, p<0.0001). CONCLUSION: Our study demonstrates that outpatient- based pediatric diabetes education lowers healthcare cost without compromising medical outcomes. [Full article available at http://rimed.org/rimedicaljournal-2017-02.asp].

(alpha)v(beta)3 integrins and Pyk2 mediate insulin-like growth factor I activation of Src and mitogen-activated protein kinase in 3T3-L1 cells.

IGF-I stimulates cell growth through interaction of the IGF receptor with multiprotein signaling complexes. However, the mechanisms of IGF-I receptor-mediated signaling are not completely understood. We have previously shown that IGF-I-stimulated 3T3-L1 cell proliferation is dependent on Src activation of the ERK-1/2 MAPK pathway. We hypothesized that IGF-I activation of the MAPK pathway is mediated through integrin activation of Src-containing signaling complexes. The disintegrin echistatin decreased IGF-I phosphorylation of Src and MAPK, and blocking antibodies to (alpha)v and beta3 integrin subunits inhibited IGF-I activation of MAPK, suggesting that (alpha)v(beta)3 integrins mediate IGF-I mitogenic signaling. IGF-I increased ligand binding to (alpha)v(beta)3 as detected by immunofluorescent staining of ligand-induced binding site antibody and stimulated phosphorylation of the beta3 subunit, consistent with inside-out activation of (alpha)v(beta)3 integrins. IGF-I increased tyrosine phosphorylation of the focal adhesion kinase (FAK) Pyk2 (calcium-dependent proline-rich tyrosine kinase-2) to a much greater extent than FAK, and increased association of Src with Pyk2 but not FAK. The intracellular calcium chelator BAPTA prevented IGF-I phosphorylation of Pyk2, Src, and MAPK, suggesting that IGF-I activation of Pyk2 is calcium dependent. Transient transfection with a dominant-negative Pyk2, which lacks the autophosphorylation and Src binding site, decreased IGF-I activation of MAPK, but no inhibition was seen with transfected wild-type Pyk2. These results indicate that IGF-I signaling to MAPK is dependent on inside-out activation of (alpha)v(beta)3 integrins and integrin-facilitated multiprotein complex formation involving Pyk2 activation and association with Src.

Efficacy of growth hormone therapy in Kearns-Sayre syndrome: the KIGS experience.

Kearns-Sayre syndrome (KSS) is characterized by external ophthalmoplegia, retinal pigmentation and cardiac conduction defects due to mitochondrial DNA (mtDNA) deletions. Short stature and growth hormone (GH) deficiency have been reported in KSS, but data on GH treatment is limited. We describe the clinical presentation, phenotype evolution, and response to GH in a patient with KSS and report data on eight additional KSS patients from the KIGS database. Our patient with KSS and GH deficiency achieved a final adult height at -0.8 SDS. In the KIGS database GH treatment resulted in mean improvement in height from -3.9 to -2.9 SDS in patients with KSS. Two patients did not show growth improvement. Our data shows improvement in height SDS in our patient and mixed results in eight additional patients from the KIGS database after treatment with GH. Heterogeneity in responsiveness may relate to presence of GH deficiency or severity of underlying mitochondrial dysfunction.

Screening and Treatment of Common Lipid Disorders in Adolescents.

Cardiovascular disease remains a substantial health care burden in the adult population, the roots of which begin in childhood. Universal screening for dyslipidemia in all children and adolescents has been implemented to identify cases of FH that are otherwise missed by conventional screening because untreated FH can result in early CVD and untimely death. Recommendations for medical therapy did not change with the 2011 NHLBI guidelines. LDL levels targeted for therapy usually are elevated because of primary genetic disorders such as FH. Although these recommendations remain controversial, the benefit of universal screening and subsequent treatment of high-risk patients far outweighs the risk of not screening, although more investigation is warranted to understand the long-term outcomes of CVD risk in youth.

Rare complications of pediatric diabetic ketoacidosis.

The incidence of type 1 diabetes (T1D) among youth is steadily increasing across the world. Up to a third of pediatric patients with T1D present with diabetic ketoacidosis, a diagnosis that continues to be the leading cause of death in this population. Cerebral edema is the most common rare complication of diabetic ketoacidosis in children. Accordingly, treatment and outcome measures of cerebral edema are vastly researched and the pathophysiology is recently the subject of much debate. Nevertheless, cerebral edema is not the only sequela of diabetic ketoacidosis that warrants close monitoring. The medical literature details various other complications in children with diabetic ketoacidosis, including hypercoagulability leading to stroke and deep vein thrombosis, rhabdomyolysis, pulmonary and gastrointestinal complications, and long-term memory dysfunction. We review the pathophysiology, reported cases, management, and outcomes of each of these rare complications in children. As the incidence of T1D continues to rise, practitioners will care for an increasing number of pediatric patients with diabetic ketoacidosis and should be aware of the various systems that may be affected in both the acute and chronic setting.

C-terminal Src kinase (CSK) modulates insulin-like growth factor-I signaling through Src in 3T3-L1 differentiation.

IGF-I stimulates both proliferation and differentiation of adipocyte-precursor cells, preadipocytes in vivo and in vitro. We have previously shown that IGF-I stimulates proliferation of 3T3-L1 preadipocytes through activation of MAPK and MAPK activation by IGF-I is mediated through the Src family of nonreceptor tyrosine kinases. In addition, we have shown that when 3T3-L1 cells reach growth arrest and are stimulated to differentiate, IGF-I can no longer activate the MAPK pathway. We hypothesized that the loss of IGF-I signaling to MAPK in differentiating 3T3-L1 cells is due to loss of IGF-I activation of Src family kinases. We measured c-Src kinase activity in cell lysates from proliferating, growth-arrested and differentiating 3T3-L1 cells. Src activity increased 2- to 4-fold in IGF-I-stimulated proliferating cells; however, IGF-I had a marginal affect on Src activity in growth-arrested cells and inhibited Src activity localized at the membrane in differentiating cells. C-terminal Src kinase (CSK), a ubiquitously expressed nonreceptor tyrosine kinase, negatively regulates the Src family kinases by phosphorylation of the Src C-terminal tyrosine. IGF-I decreased phosphorylation of the Src C-terminal tyrosine in proliferating cells and increased phosphorylation of this site in differentiating cells. IGF-I stimulated CSK kinase activity 2-fold in differentiating 3T3-L1 cells. An association between CSK and c-Src was detected by immunoprecipitation following IGF-I stimulation of differentiating but not proliferating 3T3-L1 cells. These results suggest that the loss of IGF-I downstream mitogenic signaling in differentiating 3T3-L1 cells is due to a change in IGF-I activation of c-Src and CSK may mediate the inactivation of c-Src by IGF-I in 3T3-L1 adipogenesis.

Insulin resistance syndrome in women with prior history of gestational diabetes mellitus.

The purpose of this study was to determine the prevalence of insulin resistance syndrome (IRS) and the risk factors for developing IRS among women with a history of gestational diabetes mellitus (GDM), compared with controls over 11 postdelivery years. Assessments of 106 women with a prior history of GDM and 101 controls were done on six occasions from 4-11 yr after delivery. Tests included glucose, insulin, lipids, blood pressure, and body measurements. The risk of IRS was analyzed by Cox regression. The results were that 27.2% of GDM and 8.2% of controls developed IRS by 11 yr after delivery. The hazard of developing IRS was 5.6 times (95% confidence interval = 2.6-12.3) among women with prepregnant obesity (body mass index >27.3 kg/m(2)), compared with women without prepregnant obesity and 4.4 times (95% confidence interval = 1.7-11.1) in women with a history of GDM, compared with controls. At 11 yr after delivery, the cumulative hazard for developing IRS in the next 2 yr was 26 times higher among GDM with prepregnant obesity, compared with controls without prepregnant obesity. We concluded that obesity and GDM in a prior pregnancy are significant risk factors for developing IRS over time. Early detection of markers of IRS is vital for possible prevention of type 2 diabetes and cardiovascular adverse events in women.

Glycemic control in familial vs. sporadic type 1 diabetes patients over 5 years.

BACKGROUND: Studies have shown that familial type 1 diabetes patients (FTID) have less severe metabolic derangement at presentation compared to sporadic patients (ST1D), but data on long-term metabolic control are lacking. OBJECTIVE/HYPOTHESIS: (1) FT1D will have less severe presentation and better HbA1c over 5 years compared to ST1D; (2) HbA1c in the offspring will correlate with parent HbA1c in parent-offspring group; and (3) HbA1c of the second affected sibling (SP2) will correlate with the first affected sibling (SP1) in sib-pairs. METHODS: Cohort of 33 parent-offspring and 19 sib-pairs; controls included 33 sporadic subjects matched by age, sex, ethnicity, puberty, and insulin regimen. Paired t-test and Pearson's correlation were used for statistical analysis. RESULTS: At diagnosis, mean age in FT1D vs. matched ST1D (7.7±4.9 vs. 7.6±4.5 years), mean HbA1c (9.6% vs. 10.7%), HCO3 (21 vs. 18 meq/L), glucose (428 vs. 463 mg/dL) and pH (7.35 vs. 7.36; p=ns) were not different. At 5 years, HbA1c (8.9% vs. 8.8%; p=0.81), clinic visits (12 vs. 12.5, p=0.68) and emergency room visits (0.48 vs. 0.24, p=0.10) were not different. In affected siblings, only HCO3 was different (SP1:18 vs. SP2: 24 meq/L; p<0.01). HbA1c for SP2 correlated positively with SP1 (r=0.67, p<0.01). Offspring HbA1c correlated positively with affected parents (9.3% vs. 8.6%, r=0.57, p=0.18) but was not significant. CONCLUSION: Metabolic control at diagnosis and at 5 years was similar in FT1D and ST1D. In sib-pairs, the second affected sibling had milder clinical presentation compared to the first affected sibling.